PTEN (phosphatase and tensin homolog deleted on chromosome 10) encodes a dual lipid and protein phosphatase that plays a crucial role in the phosphatidylinositol-3-kinase–Akt–mammalian-target- of-rapamycin (PI3K-AKT-mTOR) signaling pathway. PTEN function antagonizes PI3K by catalyzing the dephosphorylation

710 INTRODUCTION PTEN (phosphatase and tensin homolog deleted on chromosome 10) encodes a dual lipid and protein phosphatase that plays a crucial role in the phosphatidylinositol-3-kinase–Akt–mammalian-targetof-rapamycin (PI3K-AKT-mTOR) signaling pathway. PTEN function antagonizes PI3K by catalyzing the dephosphorylation of phosphatidylinositol (3,4,5)-trisphosphate [PIP3; also known as PtdIns(3,4,5)P3] to phosphatidylinositol (4,5)-bisphosphate [PIP2; also known as PtdIns(4,5)P2] (Maehama and Dixon, 1998; Myers et al., 1997). Loss of PTEN function leads to increased levels of PIP3 and a potent activation of 3-phosphoinositide-dependent kinase (PDK) and Akt that stimulates cell growth and survival (Song et al., 2012; Stambolic et al., 1998; Sun et al., 1999). PTEN is one of the most frequently mutated tumor suppressor genes in human cancers. The tumor suppressive function of PTEN is attributed to chromosome region 10q23, which is partially or completely deleted in multiple neoplasias (Li et al., 1997; Steck et al., 1997). Soon after, germline mutations of the PTEN gene were identified in patients with Cowden disease (Liaw et al., 1997). Since then, loss-of-function mutations of PTEN have been reported in many human sporadic cancers, including glioblastoma and thyroid, breast, colon, prostate or endometrial carcinomas, as well as in familiar cancer predisposition syndromes known as PTEN tumor hamartoma syndromes (PTHS) (Hollander et al., 2011). PTEN-knockout (KO) mouse models have provided evidence for the role of PTEN in carcinogenesis. Mice with monoallelic deletion of PTEN (PTEN+/−) develop neoplasms in multiple organs, including the endometrium, breast, prostate, gastrointestinal tract, thyroid and lymphoid tissues (Di Cristofano et al., 1998; Podsypanina et al., 1999; Suzuki et al., 1998). PTEN+/− provides a good tool to model the neoplastic phenotype observed in individuals with PTHS (Stambolic et al., 2000). Unfortunately, the embryonic lethality of mice with biallelic excision of PTEN has limited the study of complete PTEN ablation in the development of cancer. Such limitation has been solved by the generation of PTEN conditional-KO mice, which carry both PTEN alleles flanked by loxP sites (Lesche et al., 2002). To generate spatial and temporal control of PTEN deletion, conditional-KO mice have been bred with mouse strains expressing Cre recombinase under tissuespecific or inducible promoters. Such a strategy allowed biallelic ablation of PTEN in different cell types or organs (Knobbe et al., 2008; Suzuki et al., 2008), such as the adrenal gland (Korpershoek et al., 2009), breast (Li et al., 2002), thyroid (Yeager et al., 2007), prostate (Ma et al., 2005; Wang et al., 2003), astrocytes (Fraser et Disease Models & Mechanisms 6, 710-720 (2013) doi:10.1242/dmm.011445